tbuckley/cabot-search huggingface dataset:
Bone Marrow and Bone Tissue. Color Atlas of Clinical Histopathology.
Authors: Rolf Burkhardt
Journal: Annals of Internal Medicine (1973)

This is a well produced and excellently illustrated study of the normal anatomy of the neonatal skull; it contains also a section on the normal variants to be found and an extensive review of the pathological conditions which from time to time occur in the skull of the neonate.The latter part is divided into sections, those of greatest value to the anatomist being the first one on abnormalities in size and shape, and a later section on the role of the skull in obstetrics, in which, besides an account of pathological states, there is a very good commentary, with illustrations, on the skull in early pregnancy diagnosis and on moulding.The normal anatomy is clearly and simply, yet fully, described.I liked particularly the clear definitions of the sutures and the excellent general views and illustrations of the newborn skull.This book will be of great value to all those preparing lectures and tutorials and also as a reference book for students.M.
O-alg-THAM/gel hydrogels functionalized with engineered microspheres based on mesenchymal stem cell secretion recruit endogenous stem cells for cartilage repair
Authors: Yucong Li, Linlong Li, Ming Wang, Boguang Yang, Baozhen Huang, Shanshan Bai, Xiaoting Zhang, Nan Hou, Haixing Wang, Zhengmeng Yang, Chong Tang, Ye Li, Wayne Yuk-Wai Lee, Lu Feng, Micky D. Tortorella, Gang Li
Journal: Bioactive Materials (2023)

Lacking self-repair abilities, injuries to articular cartilage can lead to cartilage degeneration and ultimately result in osteoarthritis. Tissue engineering based on functional bioactive scaffolds are emerging as promising approaches for articular cartilage regeneration and repair. Although the use of cell-laden scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent, these approaches are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. Acellular approaches through the recruitment of endogenous cells offer great promise for in situ articular cartilage regeneration. In this study, we propose an endogenous stem cell recruitment strategy for cartilage repair. Based on an injectable, adhesive and self-healable o-alg-THAM/gel hydrogel system as scaffolds and a biophysio-enhanced bioactive microspheres engineered based on hBMSCs secretion during chondrogenic differentiation as bioactive supplement, the as proposed functional material effectively and specifically recruit endogenous stem cells for cartilage repair, providing new insights into in situ articular cartilage regeneration.
M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator
Authors: Yili Wang, Qiushui Lin, Hao Zhang, Sicheng Wang, Jin Cui, Yan Hu, Jinlong Liu, Mengmeng Li, Kun Zhang, Fengjin Zhou, Yingying Jing, Zhen Geng, Jiacan Su
Journal: Bioactive Materials (2023)

Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing. Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes, which respectively exhibit pro-inflammatory or anti-inflammatory functions. Therefore, modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing. Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity. In this study, we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures. The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages, thereby accelerating diabetic fracture healing. We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway. Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.
Two to tango: endothelial cell TMEM16 scramblases drive coagulation and thrombosis
Authors: János G. Filep
Journal: Journal of Clinical Investigation (2023)

Endothelial cells form a constitutively anticoagulant surface under homeostasis. While loss of this anticoagulant property is a hallmark of many cardiovascular diseases, the molecular mechanisms underlying the procoagulant transition remain incompletely understood. In this issue of the JCI, Schmaier et al. identify the phospholipid scramblases TMEM16E and TMEM16F, which support endothelial procoagulant activity through phosphatidylserine (PS) externalization. Genetic deletion of TMEM16E or TMEM16F or treatment with TMEM16 inhibitors prevented PS externalization and reduced fibrin formation in the vessel wall independently of platelets in a murine laser-injury model of thrombosis. These findings reveal a role for endothelial TMEM16E in thrombosis and identify TMEM16E as a potential therapeutic target for preventing thrombus formation.
Time of day for COVID vaccine administration linked to clinical effectiveness
Authors: Laura J. Rasmussen-Torvik
Journal: Journal of Clinical Investigation (2023)

Time of day for COVID vaccine administration linked to clinical effectivenessIn this issue of the JCI, Hazan et al. (1) report on whether time of day of COVID vaccination associates with subsequent breakthrough COVID-19 infection in 1,515,754 patients, using data from a large Israeli health maintenance organization.The authors found evidence to support that the timing of vaccine dosing associated with clinical outcomes.When considering the timing of the second dose in the original two-dose COVID vaccine series, individuals who were vaccinated in the morning (0800-1159 hours) had lower rates of breakthrough infections, emergency room visits for COVID, and hospitalizations for COVID when compared with individuals vaccinated in the evening
Hierarchical Interleaved Bloom Filter: enabling ultrafast, approximate sequence queries
Authors: Svenja Mehringer, Enrico Seiler, Felix Droop, Mitra Darvish, René Rahn, Martin Vingron, Knut Reinert
Journal: Genome biology (2023)

Abstract We present a novel data structure for searching sequences in large databases: the Hierarchical Interleaved Bloom Filter (HIBF). It is extremely fast and space efficient, yet so general that it could serve as the underlying engine for many applications. We show that the HIBF is superior in build time, index size, and search time while achieving a comparable or better accuracy compared to other state-of-the-art tools. The HIBF builds an index up to 211 times faster, using up to 14 times less space, and can answer approximate membership queries faster by a factor of up to 129.
Preparing for the next viral threat with broad-spectrum antivirals
Authors: Marwah Karim, Chieh-Wen Lo, Shirit Einav
Journal: Journal of Clinical Investigation (2023)

There is a large global unmet need for the development of countermeasures to combat hundreds of viruses known to cause human disease and for the establishment of a therapeutic portfolio for future pandemic preparedness. Most approved antiviral therapeutics target proteins encoded by a single virus, providing a narrow spectrum of coverage. This, combined with the slow pace and high cost of drug development, limits the scalability of this direct-acting antiviral (DAA) approach. Here, we summarize progress and challenges in the development of broad-spectrum antivirals that target either viral elements (proteins, genome structures, and lipid envelopes) or cellular proviral factors co-opted by multiple viruses via newly discovered compounds or repurposing of approved drugs. These strategies offer new means for developing therapeutics against both existing and emerging viral threats that complement DAAs.
Reporting on FH-deficient renal cell carcinoma using circulating succinylated metabolites
Authors: Divya Bezwada, James Brugarolas
Journal: Journal of Clinical Investigation (2023)

Fumarate hydratase-deficient (FH-deficient) renal cell carcinoma (RCC) represents a particularly aggressive form of kidney cancer. FH-deficient RCC arises in the setting of germline, or solely somatic, mutations in the FH gene, a two-hit tumor suppressor gene. Early detection can be curative, but there are no biomarkers, and in the sporadic setting, establishing a diagnosis of FH-deficient RCC is challenging. In this issue of the JCI, Zheng, Zhu, and co-authors report untargeted plasma metabolomic analyses to identify putative biomarkers. They discovered two plasma metabolites directly linked to fumarate overproduction by tumor cells, succinyl-adenosine and succinic-cysteine, which correlate with tumor burden. The identification of circulating biomarkers of FH-deficient RCC may aid in the diagnosis of FH-deficient RCC and provide a means for longitudinal follow-up.
Prognosis of immune checkpoint inhibitors-induced myocarditis: a case series
Authors: Cyrille Coustal, Juliette Vanoverschelde, Xavier Quantin, Candice Lesage, Jean-Marie Michot, Ariane Lappara, Stephane Ederhy, Eric Assenat, Maxime Faure, Nahema Issa, Olivier Lambotte, Mathieu Puyade, Olivier Dereure, Diego Tosi, Patricia Rullier, Isabelle Serre, Romaric Larcher, Kada Klouche, Gérald Chanques, Hélène Vernhet-Kovacsik, Jean-Luc Faillie, Audrey Agullo, François Roubille, Philippe Guilpain, Alexandre Thibault Jacques Maria
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening.
Early effects of acetazolamide on hemoglobin mass and plasma volume in chronic mountain sickness at 5100 m
Authors: B. Champigneulle, E. Stauffer, P. Robach, S. Doutreleau, C.A. Howe, A. Pina, A.A. Salazar-Granara, I. Hancco, D. Guergour, J.V. Brugniaux, P. Connes, A. Pichon, S. Verges
Journal: Pulmonology (2023)

Chronic Mountain Sickness (CMS) syndrome, combining excessive erythrocytosis and clinical symptoms in highlanders, remains a public health concern in high-altitude areas, especially in the Andes, with limited therapeutic approaches. The objectives of this study were to assess in CMS-highlanders permanently living in La Rinconada (5100-5300 m, Peru, the highest city in the world), the early efficacy of acetazolamide (ACZ) and atorvastatin to reduce hematocrit (Hct), as well as the underlying mechanisms focusing on intravascular volumes.Forty-one males (46±8 years of age) permanently living in La Rinconada for 15 [10-20] years and suffering from CMS were randomized between ACZ (250 mg once-daily; N = 13), atorvastatin (20 mg once-daily; N = 14) or placebo (N = 14) uptake in a double-blinded parallel study. Hematocrit (primary endpoint) as well as arterial blood gasses, total hemoglobin mass (Hbmass) and intravascular volumes were assessed at baseline and after a mean (±SD) treatment duration of 19±2 days.ACZ increased PaO2 by +13.4% (95% CI: 4.3 to 22.5%) and decreased Hct by -5.2% (95% CI: -8.3 to -2.2%), whereas Hct remained unchanged with placebo or atorvastatin. ACZ tended to decrease Hbmass (-2.6%, 95% CI: -5.7 to 0.5%), decreased total red blood cell volume (RBCV, -5.3%, 95% CI: -10.3 to -0.3%) and increased plasma volume (PV, +17.6%, 95% CI: 4.9 to 30.3%). Atorvastatin had no effect on intravascular volumes, while Hbmass and RBCV increased in the placebo group (+6.1%, 95% CI: 4.2 to 7.9% and +7.0%, 95%CI: 2.7 to 11.4%, respectively).Short-term ACZ uptake was effective to reduce Hct in CMS-highlanders living at extreme altitude >5,000 m and was associated with both an increase in PV and a reduction in RBCV.
Polymerase θ inhibition steps on the cGAS pedal
Authors: Chelsea M. Smith, Gaorav P. Gupta
Journal: Journal of Clinical Investigation (2023)

Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by mediating error-prone double-stranded break (DSB) repair and facilitating resistance against poly-ADP ribose polymerase inhibitor treatment. In this issue of the JCI, Oh, Wang, et al. report on the impact of Pol θ inhibition on activation of antitumor immunity. The authors used pancreatic ductal adenocarcinoma (PDAC) cell and mouse models characterized by HR-associated gene alterations and POLQ overexpression. POLQ knockdown showed synthetic lethality in combination with gene mutations involving DNA repair, including BRCA1, BRCA2, and ATM. Notably, Pol θ deficiency or inhibition suppressed tumor growth, increased the accumulation of unrepaired DNA damage, and enhanced T cell infiltration via the cGAS/STING pathway. These findings suggest a broader scope for Pol θ inhibition in HR-deficient cancers.
The digital transformation of surgery
Authors: Jayson S. Marwaha, Marium M. Raza, Joseph C. Kvedar
Journal: npj Digital Medicine (2023)

Rapid advances in digital technology and artificial intelligence in recent years have already begun to transform many industries, and are beginning to make headway into healthcare. There is tremendous potential for new digital technologies to improve the care of surgical patients. In this piece, we highlight work being done to advance surgical care using machine learning, computer vision, wearable devices, remote patient monitoring, and virtual and augmented reality. We describe ways these technologies can be used to improve the practice of surgery, and discuss opportunities and challenges to their widespread adoption and use in operating rooms and at the bedside.
Cell surface marker-based capture of neoantigen-reactive CD8<sup>+</sup>T-cell receptors from metastatic tumor digests
Authors: Praveen D Chatani, Frank J Lowery, Neilesh B Parikh, Kyle J Hitscherich, Rami Yossef, Victoria Hill, Jared J Gartner, Biman Paria, Maria Florentin, Satyajit Ray, Alakesh Bera, Maria Parkhust, Paul Robbins, Sri Krishna, Steven A Rosenberg
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Cellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to the forefront of clinical investigation, the rapid, scalable, and cost-effective detection of patient-specific neoantigen-reactive TIL remains a top priority. Methods We analyzed the single-cell transcriptomic states of 31 neoantigen-specific T-cell clonotypes to identify cell surface dysfunction markers that best identified the metastatic transcriptional states enriched with antitumor TIL. We developed an efficient method to capture neoantigen-reactive TCRs directly from resected human tumors based on cell surface co-expression of CD39, programmed cell death protein-1, and TIGIT dysfunction markers (CD8 + TIL TP ). Results TIL TP TCR isolation achieved a high degree of correlation with single-cell transcriptomic signatures that identify neoantigen-reactive TCRs, making it a cost-effective strategy using widely available resources. Reconstruction of additional TIL TP TCRs from tumors identified known and novel antitumor TCRs, showing that at least 39.5% of TIL TP TCRs are neoantigen-reactive or tumor-reactive. Despite their substantial enrichment for neoantigen-reactive TCR clonotypes, clonal dynamics of 24 unique antitumor TIL TP clonotypes from four patients indicated that most in vitro expanded TIL TP populations failed to demonstrate neoantigen reactivity, either by loss of neoantigen-reactive clones during TIL expansion, or through functional impairment during cognate neoantigen recognition. Conclusions While direct usage of in vitro-expanded CD8 + TIL TP as a source for cellular therapy might be precluded by profound TIL dysfunction, isolating TIL TP represents a streamlined effective approach to rapidly identify neoantigen-reactive TCRs to design engineered cellular immunotherapies against cancer.
Nontargeted metabolomics analysis of follicular fluid in patients with endometriosis provides a new direction for the study of oocyte quality
Authors: Yiqiu Wei, Zhourui Zhang, Yaoyao Zhang, Jianan Li, Xianqin Ruan, Qiongqiong Wan, Tailang Yin, Yujie Zou, Suming Chen, Yan Zhang
Journal: MedComm (2023)

Endometriosis is a common, estrogen-dependent chronic gynecological disease that endangers the reproductive system and systemic metabolism of patients. We aimed to investigate the differences in metabolic profiles in the follicular fluid between infertile patients with endometriosis and controls. A total of 25 infertile patients with endometriosis and 25 infertile controls who were similar in age, BMI, fertilization method and ovulation induction treatment were recruited in this study. Metabolomics analysis of follicular fluid was performed by two methods of high-performance liquid chromatography tandem mass spectrometry. There were 36 upregulated and 17 downregulated metabolites in the follicular fluid of patients in the endometriosis group. KEGG pathway analysis revealed that these metabolites were enriched in phenylalanine, tyrosine and tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine metabolism and pyrimidine metabolism pathways. A biomarker panel consisting of 20 metabolites was constructed by random forest, with an accuracy of 0.946 and an AUC of 0.988. This study characterizes differences in follicular fluid metabolites and associated pathway profiles in infertile patients with endometriosis. These findings can provide a better comprehensive understanding of the disease and a new direction for the study of oocyte quality, as well as potential metabolic markers for the prognosis of endometriosis.
IL-6 helps weave the inflammatory web during acute coronary syndromes
Authors: Tetsushi Nakao, Peter Libby
Journal: Journal of Clinical Investigation (2023)

The cytokine IL-6 has well-known proinflammatory roles in aging and ischemic heart disease. In this issue of the JCI, Alter and colleagues used mouse experiments and human tissue to investigate the source of IL-6 following myocardial infarction. The authors showed that cardiac fibroblasts produced IL-6 after coronary ligation in mice and proposed the existence of a pathway involving adenosine signaling via the adenosine A2b receptor. The findings underscore the complexity of IL-6 biology in ischemic heart disease and identify an adenosine/IL-6 pathway that warrants consideration for targeting as a modulator of cardiovascular risk.
Micromechanical interlocking structure at the filler/resin interface for dental composites: a review
Authors: Shuning Zhang, Xiao Wang, Jiawei Yang, Hongyan Chen, Xinquan Jiang
Journal: International Journal of Oral Science (2023)

Abstract Dental resin composites (DRCs) are popular materials for repairing caries or dental defect, requiring excellent properties to cope with the complex oral environment. Filler/resin interface interaction has a significant impact on the physicochemical/biological properties and service life of DRCs. Various chemical and physical modification methods on filler/resin interface have been introduced and studied, and the physical micromechanical interlocking caused by the modification of fillers morphology and structure is a promising method. This paper firstly introduces the composition and development of DRCs, then reviews the chemical and physical modification methods of the filler/resin interface, mainly discusses the interface micromechanical interlocking structures and their enhancement mechanism for DRCs, finally give a summary on the existing problems and development potential.
Looking for answers far away from the soma—the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS
Authors: Ariel Ionescu, Topaz Altman, Eran Perlson
Journal: Molecular Neurodegeneration (2023)

Abstract Axon degeneration and Neuromuscular Junction (NMJ) disruption are key pathologies in the fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Despite accumulating evidence that axons and NMJs are impacted at a very early stage of the disease, current knowledge about the mechanisms leading to their degeneration remains elusive. Cytoplasmic mislocalization and accumulation of the protein TDP-43 are considered key pathological hallmarks of ALS, as they occur in ~ 97% of ALS patients, both sporadic and familial. Recent studies have identified pathological accumulation of TDP-43 in intramuscular nerves of muscle biopsies collected from pre-diagnosed, early symptomatic ALS patients. These findings suggest a gain of function for TDP-43 in axons, which might facilitate early NMJ disruption. In this review, we dissect the process leading to axonal TDP-43 accumulation and phosphorylation, discuss the known and hypothesized roles TDP-43 plays in healthy axons, and review possible mechanisms that connect TDP-43 pathology to the axon and NMJ degeneration in ALS.
Association between domesticated animal ownership and Plasmodium falciparum parasite prevalence in the Democratic Republic of the Congo: a national cross-sectional study
Authors: Camille E Morgan, Hillary M Topazian, Katerina Brandt, Cedar Mitchell, Melchior Mwandagalirwa Kashamuka, Jérémie Muwonga, Eric Sompwe, Jonathan J Juliano, Thierry Bobanga, Antoinette Tshefu, Michael Emch, Jonathan B Parr
Journal: The Lancet Microbe (2023)

BackgroundDomesticated animal ownership is an understudied aspect of the human environment that influences mosquito biting behaviour and malaria transmission, and is a key part of national economies and livelihoods in malaria-endemic regions. In this study, we aimed to understand differences in Plasmodium falciparum prevalence by ownership status of common domesticated animals in DR Congo, where 12% of the world's malaria cases occur and anthropophilic Anopheles gambiae vectors predominate.MethodsIn this cross-sectional study, we used survey data from individuals aged 15–59 years in the most recent (2013–14) DR Congo Demographic and Health Survey and previously performed Plasmodium quantitative real-time PCR (qPCR) to estimate P falciparum prevalence differences by household ownership of cattle; chickens; donkeys, horses, or mules; ducks; goats; sheep; and pigs. We used directed acyclic graphs to consider confounding by age, gender, wealth, modern housing, treated bednet use, agricultural land ownership, province, and rural location.FindingsOf 17 701 participants who had qPCR results and covariate data, 8917 (50·4%) of whom owned a domesticated animal, we observed large differences in malaria prevalence across types of animals owned in both crude and adjusted models. Household chicken ownership was associated with 3·9 (95% CI 0·6 to 7·1) more P falciparum infections per 100 people, whereas cattle ownership was associated with 9·6 (–15·8 to –3·5) fewer P falciparum infections per 100 people, even after accounting for bednet use, wealth, and housing structure.InterpretationOur finding of a protective association conferred by cattle ownership suggests that zooprophylaxis interventions might have a role in DR Congo, possibly by drawing An gambiae feeding away from humans. Studies of animal husbandry practices and associated mosquito behaviours could reveal opportunities for new malaria interventions.FundingThe National Institutes of Health and the Bill & Melinda Gates Foundation.TranslationsFor the French and Lingala translations of the abstract see Supplementary Materials section.